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Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)

27 luglio 2017 aggiornato da: University Hospital, Tours

Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab in Patients Older Than 65 Years With Previously Untreated Chronic Lymphocytic Leukemia: a Phase III Trial of FILO

RATIONALE: Classical chemotherapy does not cure advanced chronic lymphocytic leukemia (CLL) despite new drugs. Rituximab is a monoclonal antibody directed against CD20 surface antigen on B lymphocytes and leads to apoptosis of CD20 positive B lymphocytes. The highest response rate yet published in the treatment of first-line CLL has been obtained by the association of fludarabine, cyclophosphamide and rituximab (FCR). Now, the question is whether this response can be improved, as some trials showed that eradication of minimal residual disease (MRD) in CLL is associated with a longer treatment-free and overall survival. Maintenance therapy using rituximab has been recently approved as a means of prolonging remission in patients with indolent non Hodgkin's lymphoma. Maintenance therapy with rituximab could be of interest in treatment of MRD in CLL and prolonging remission and survival times.

PURPOSE: The overall purpose of the study is to determine the value of immunotherapy maintenance with single agent rituximab in comparison with no further treatment (observation ) for previously untreated chronic lymphocytic leukaemia in elderly (>65 years) patients who respond to induction immunochemotherapy with FCR.

Panoramica dello studio

Stato

Completato

Condizioni

Intervento / Trattamento

Descrizione dettagliata

OBJECTIVES:

Primary

  • To demonstrate superiority, in terms of 3-year progression-free survival (PFS), of rituximab maintenance over observation in patients who are in complete or partial response (CR or PR) after induction therapy comprising fludarabine, cyclophosphamide, and rituximab.

Secondary

  • To determine event-free survival, disease-free survival, overall survival, and time to next treatment, all from time of randomization.
  • To determine overall response rate (CR and PR) according to NCI and iwCLL criteria
  • To assess the rate of phenotypic response (minimal residual disease).
  • To assess duration of phenotypic and NCI and iwCLL clinical responses.
  • To determine response rates and time-related parameters in biological subgroups.
  • To determine rates of treatment-related adverse events.
  • To evaluate CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia.
  • To study pharmacokinetics of rituximab during induction and maintenance.
  • To evaluate the prognostic impact of the immunoglobulin FcγRIIIA genotype.
  • To assess quality of life.
  • To study pharmacoeconomics.

OUTLINE: This is a multicenter study. Randomization is stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IGHV mutational status, and 11q deletion.

Patients receive rituximab IV on days 1 and 14 of courses 1-2 and on day 1 of courses 3 and 4. Patients also receive oral fludarabine and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses are administered every 28 days. Patients achieving CR or PR are randomized 1:1 to maintenance arm or observation arm.

  • Arm A: Patients receive rituximab IV every 2 months in the absence of disease progression or unacceptable toxicity for a maximum duration of 24 months (12 infusions).
  • Arm B: Patients undergo observation only.

After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 2 years.

Tipo di studio

Interventistico

Iscrizione (Effettivo)

542

Fase

  • Fase 3

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Francia
      • TOURS Cedex, Francia, 37044
        • French Innovative Leukemia Organization

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

65 anni e precedenti (Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

Inclusion criteria

  • B-CLL
  • Matutes score 4 or 5
  • Binet stages B or C
  • Age > 65 years old
  • No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy, except glucocorticoids < 1 month
  • Patient's written informed consent
  • Life expectancy > 6 months

Exclusion criteria

  • Binet stage A
  • ECOG performance status 2 or more
  • Presence of a 17p deletion by FISH (> 10% positive cores)
  • Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
  • Patients with a history of another malignancy in complete remission less than 5 years, except basal cell skin cancer or tumor treated curatively by surgery
  • Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
  • Any severe co-morbidities such as NYHA Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia, or uncontrolled diabetes mellitus.
  • CIRS (Cumulative Illness rating Scale) > 6
  • Known hypersensitivity to murine proteins or to any of the study drugs or to their components
  • Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma) or prolymphocytic leukemia
  • Active bacterial, viral or fungal infection
  • Seropositivity HIV, hepatitis C or hepatitis B (unless clearly due to vaccination)
  • Total bilirubin, alkaline phosphatases and aminotransferases > 2 x ULN
  • Creatinine clearance < 60 ml/min calculated according to the formula of Cockcroft and Gault
  • Any coexisting medical or psychological condition that would preclude participation to the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment

Inclusion criteria at randomization

  • Patients having received the full induction phase with 4 FC and 6 rituximab courses (with/without dose adjustments as per protocol)
  • Complete or partial response according to NCI and iwCLL criteria at the end of induction phase
  • Recovery from FCR toxicities
  • Patient willingness to continue on protocol

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Nessun intervento: Observation
Observation every 8 weeks during 2 years
Sperimentale: rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
Biologico: Rituximab
rituximab :500 mg/m² every 8 weeks during 2 years
Altri nomi:
  • Mabthera

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Progression-free survival
Lasso di tempo: randomization until disease progression or death
Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria
randomization until disease progression or death

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Event-free survival
Lasso di tempo: randomization until disease progression, death, new CLL treatment, and secondary cancer
Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
randomization until disease progression, death, new CLL treatment, and secondary cancer
Disease-free survival
Lasso di tempo: first documented CR until relapse
Disease-free survival is defined as the time from first documented CR to relapse
first documented CR until relapse
Overall survival
Lasso di tempo: randomization until death
Overall survival is defined as the time from randomization to death from any cause
randomization until death
Time to next treatment
Lasso di tempo: randomization until new CLL treatment
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
randomization until new CLL treatment
Overall response rate
Lasso di tempo: baseline up to approximately 66 months
Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
baseline up to approximately 66 months
Phenotypic response rate
Lasso di tempo: randomization up to approximately 60 months
Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
randomization up to approximately 60 months
Rates of treatment-related adverse events
Lasso di tempo: safety since baseline
Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
safety since baseline
Pharmacokinetics of rituximab
Lasso di tempo: baseline up to approximately 36 months
Pharmacokinetics of rituximab during induction and rituximab maintenance
baseline up to approximately 36 months
Quality of life
Lasso di tempo: baseline up to approximately 30 months
Change from baseline in EORTC Quality of Life Questionnaire Core 30
baseline up to approximately 30 months

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

University Hospital, Tours

Collaboratori

Roche Pharma AG
French Innovative Leukemia Organisation

Investigatori

  • Investigatore principale: Caroline Dartigeas, MD, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
  • Investigatore principale: Eric VAN DEN NESTE, MD PhD, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio

1 dicembre 2007

Completamento primario (Effettivo)

1 febbraio 2014

Completamento dello studio (Effettivo)

1 luglio 2017

Date di iscrizione allo studio

Primo inviato

26 marzo 2008

Primo inviato che soddisfa i criteri di controllo qualità

26 marzo 2008

Primo Inserito (Stima)

27 marzo 2008

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

1 agosto 2017

Ultimo aggiornamento inviato che soddisfa i criteri QC

27 luglio 2017

Ultimo verificato

1 luglio 2017

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • CDR0000589684
  • CHRUT-LLC-2007-SA (Altro identificatore: CHU Tours)
  • CHRUT-PHRN05-CD (Altro identificatore: CHU Tours)
  • INCA-RECF0497 (Altro identificatore: INCA)
  • 2007-001015-28 (Numero EudraCT)

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

No

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

prodotto fabbricato ed esportato dagli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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